Secondary AML is a serious complication of alkylator-based cancer chemotherapy. We hypothesize that susceptibility to alkylator-associated AML is at least in part a genetic trait. Using complementary approaches in human and mouse models, we will analyze the genetic determinants of therapy-related AML (t-AML) with the following specific aims: Specific Aim 1. We will define the association between patients with alkylator chemotherapy-associated AML and germline polymorphisms of "alkylator pathway" and "leukemogenesis" genes. We will prepare germline DNA from microdissected pretreatment tissue samples obtained from t-AML cases and controls enrolled in cooperative clinical trials monitored by the NCI's Cancer Therapy Evaluation Program (CTEP). We will identify single nucleotide polymorphisms (SNPs) in alkylator pathway genes (e.g., alkylator metabolism, DNA repair) that are associated with increased risk of t-AML. This will assess the impact of variation in the pharmacokinetic and pharmacodynamic control of alkylator therapy. In the second component of this Aim, we will genotype cases and controls at loci implicated in the pathogenesis of de novo AML. The rationale for this comes from the observation that some genes mutated in de novo AML are mutated in the germline of patients predisposed to AML. Some of these germline alleles may also predispose patients to t-AML. Many of the candidate genes in this list will arise from the gene discovery arms of Projects 1-5 of the GAML Program Project. We will identify SNPs in these genes that are polymorphic between t-AML cases and controls. Specific Aim 2. We will perform a genetic screen in mice to identify novel loci associated with alkylator chemotherapy-associated AML. We will develop a mouse model of alkylator-induced AML. We will apply this model to a range of genetically diverse inbred strains of mice. Candidate alkylator pathway and leukemia pathogenesis genes will be resequenced in order to identify polymorphisms associated with susceptibility to t-AML in mice. Finally, QTL mapping in susceptible and resistant strains will be utilized to identify additional genomic loci that are associated with the t-AML phenotype. Information gained from the human and mouse components of this project complement each other. Candidate susceptibility polymorphisms will be validated in mouse models. Improved understanding of the genetic determinants of susceptibility to t-AML has great potential to improve the care of cancer patients.